Controlled release therapeutic wound dressings

ABSTRACT

A wound dressing comprising: a therapeutic agent selected from the group consisting of antimicrobial substances, pain relieving substances, protease inhibitors, and mixtures thereof; and a barrier layer for initially separating the therapeutic agent from a wound fluid in use, wherein the barrier layer comprises a substrate for an enzyme selected from the group consisting of proteases, kallikrein and tissue-plasminogen activator. Preferably the substrate comprises a substrate for elastase or a collagenase. The barrier layer breaks down in infected or chronic wounds, thereby releasing the therapeutic substance selectively into such wounds.

The present invention relates to wound dressing materials, and inparticular to new materials for the controlled release of therapeuticagents into wounds.

In mammals, injury triggers an organised complex cascade of cellular andbiochemical events that result in a healed wound. Wound healing is acomplex dynamic process that results in the restoration of anatomiccontinuity and function; an ideally healed wound is one that hasreturned to normal anatomic structure, function and appearance.

Infection of wounds by bacteria delays the healing process, sincebacteria compete for nutrients and oxygen with macrophages andfibroblasts, whose activities are essential for the healing of thewound. Infection results when bacteria achieve dominance over thesystemic and local factors of host resistance. Infection is therefore amanifestation of a disturbed host/bacteria equilibrium in favour of theinvading bacteria. This elicits a systemic septic response, and alsoinhibits the multiple processes involved in wound healing. Lastly,infection can result in a prolonged inflammatory phase and thus slowhealing, or may cause further necrosis of the wound. The granulationphase of the healing process will begin only after the infection hassubsided.

Chronically contaminated wounds all contain tissue bacterial flora.These bacteria may be endogenous to the patient or might be exogenous tothe wound. Closure, or eventual healing of the wound is often based on aphysician's ability to control the level of the bacterial flora.

If clinicians could respond to wound infection as early as possible theinfection could be treated topically as opposed to having to useantibiotics. This would also lead to less clinicalintervention/hospitalisation and would reduce the use of antibiotics andother complications of infection.

Current methods used to identify bacterial infection rely mainly onjudgement of the odour and appearance of a wound. With experience, it ispossible to identify an infection in a wound fly certain chemical signssuch as redness or pain. Some clinicians take swabs that are thencultured in the laboratory to identify specific organisms, but thistechnique takes time.

Pain is also associated with infected and chronic wounds. Biochemically,pain is experienced when there is an increase of kinins (bradykinin) inthe area of the wound. Kinins are produced by the proteolytic breakdownof kininogen, and the protease responsible for this is kallikrein.Kallikrein also stimulates the production of tissue plasminogenactivator (t-PA)

It is also known to provide antimicrobial wound dressings. For example,such dressings, are known having a liquid permeable wound contactinglayer, an intermediate absorbent layer and an outer, liquid-imperviousbacking layer, in which one or more of the layers contains anantimicrobial agent. For example, EP-A-0599589 describes layered wounddressings having a wound contacting layer of a macromolecularhydrocolloid, an absorbent layer, and a continuous, microporous sheetintermediate the wound contacting layer and the absorbent layer. Theabsorbent layer contains a low molecular weight antimicrobial agent thatcan diffuse into the wound.

WO-A-0238097 describes wound dressings comprising a liquid-permeable topsheet having a wound facing surface and a back surface, and a hydrogellayer on the wound facing surface of the top sheet The top sheet isadapted to block or restrict passage of liquid from the back surface tothe wound facing surface. The hydrogel layer is an insoluble hydrogeladapted to maintain a moist wound healing environment at the woundsurface. The hydrogel may contain therapeutic agents such asantimicrobial agents, for sustained release into the wound.

EP-A-0518697 describes a laminated collagen film for delayed release ofmedicaments. Different layers of the film contain differentconcentrations of medicaments. The laminated films do not appear to beresponsive to wound infection.

U.S. Pat. No. 6,160,200 describes absorbent sanitary articles forabsorbing bodily waste. At least a portion of the body facing surface ofthe articles includes a material capable of dissolving in contact withbodily exudates so as to permit the bodily exudates to pass into anabsorbent layer

Previous antimicrobial wound dressings suffer from the drawback that therelease of the antimicrobial agent is relatively unresponsive to thedegree of infection of the wound being treated. This is undesirablebecause it can result in resistant microorganisms, and also because allunnecessary medication can interfere with the processes of woundhealing.

There is thus a need for a wound dressing that will selectively releaseantimicrobial agents and/or pain relieving agents into infected woundsbut not into non-infected wounds, such release into infected woundstaking place preferably even prior to obvious clinical symptoms ofinfection. Such a dressing would provide early intervention withsuitable treatment (e.g. a topical antimicrobial treatment) before woundchronicity sets in.

It has now been discovered that wound fluid from wounds that areapparently not clinically infected but which go on to become infectedwithin a few days have high levels of neutrophil elastase activity andmay also have high levels of other inflammatory enzymes, such asmacrophage proteases, other neutrophil proteases, bacterial collagenase,plasmin, hyaluronidase, kallikrein or t-PA.

It is known that chronic wounds, such as venous ulcers, pressure soresand diabetic ulcers have a disordered wound healing metabolism even inthe absence of infection. In particular, wound chronicity is associatedwith elevated levels of protease enzymes in the wound that interferewith the normal processes of tissue formation and destruction in thewound.

The present invention provides a wound dressing comprising: atherapeutic agent selected from the group consisting of antimicrobialsubstances, pain relieving substances, protease inhibitors, and mixturesthereof; and a barrier layer for initially separating the therapeuticagent from a wound fluid in use, wherein the barrier layer comprises asubstrate for an enzyme selected from the group consisting of proteases,kallikrein and tissue-plasminogen activator.

The antimicrobial agent may, for example, comprise an antiseptic, anantibiotic, or mixtures thereof. Preferred antibiotics includetetracycline, penicillins, terramycins. erythromycin, bacitracin,neomycin, polymycin B, mupirocin, clindamycin and mixtures thereof.Preferred antiseptics include silver sulfadiazine, chlorhexidine,povidone iodine, triclosan, other silver salts, sucralfate, quaternaryammonium salts and mixtures thereof. The pain relieving agent may be ananalgesic or a local anaesthetic.

The barrier layer is separate from the therapeutic agent, and thetherapeutic agent is initially prevented from contacting the wound fluidby the barrier layer. That is to say, the bioavailability of thetherapeutic agent to the wound surface is preferably initiallysubstantially zero, and remains substantially zero or low for a finitetime until the barrier material has been broken down by the enzyme, atwhich point the bioavailability increases sharply. Since the enzymelevels are elevated in infected or chronic wounds, this provides foraccelerated and/or selective release of the therapeutic agent into suchwounds. The barrier layer is normally substantially impervious to woundfluid and insoluble therein unless the wound fluid contains a sufficientlevel of the specified enzyme to break down the substrate material. Thebarrier layer is preferably substantially free of the therapeuticagents.

The protease may be a macrophage or neutrophil protease, or a human orbacterial collagenase or gelatinase. The macrophage and neutrophilproteases include elastase, matrix metalloproteinase 9 (MMP-9), MMP-8,cathepsin G, MMP-12, capases and mixtures thereof. Suitable substratesfor neutrophil elastases and Cathepsin G comprise Elastin, fibronectin,or mixtures thereof. Suitable substrates for collagenases comprisecollagen, gelatin, or mixtures thereof. Suitable substrates for plasmincomprise fibrinogen, fibrin, casein, or mixtures thereof. Suitablesubstrates for MMP's comprise collagen, gelatin, or mixtures thereof.Suitable substrates for hyaluronidases compose hyaluronic acid or saltsthereof. Suitable substrates for kallikrein comprise plasminogen,fibrinogen, or mixtures thereof. Suitable substrates for t-PA compriseplasminogen and fibrin.

The barrier layer is preferably about 0.1 to about 3 mm thick.Preferably about 0.5 to 1.5 mm thick. The enzyme substrate material maybe combined in a film-forming composition with additional polymericmaterials, plasticisers, and humectants. Suitable polymers includealginates, guar gum, carboxymethyl cellulose, methyl cellulose,hydroxypropyl methyl cellulose, locust bean gum, carrageenan, chitosan,heparan sulfate, dermatan sulfate, glycosaminoglycans such as hyaluronicacid, proteoglyrans, and mixtures thereof. Suitable plasticisers includeC2-C8 polyhydric alcohols such as glycerol. Preferably the enzymesubstrate compounds make up at least about 10% by weight, morepreferably at least about 20% by weight of the film-forming composition.

The barrier layer is preferably a flexible sheet that is conformable tothe contours of a wound, and preferably the sheet has an area of atleast about 1 cm². In certain embodiments the barrier layer comprises asubstantially continuous film comprising the film forming composition ofenzyme substrate as described above. In other embodiments the barrierlayer comprises an apertured sheet having a composition comprising thesubstrate material applied thereto in occlusive fashion. The occlusivecomposition may be similar to the film-forming composition describedabove. In these embodiments, the apertures typically make up from about0.1% to about 50% of the area of the wound facing surface of the sheetbefore swelling, more typically from about 1% to about 30% of the areaof the apertured sheet, and preferably from about 10% to about 25% ofthe area of the apertured sheet. Typically, the apertured sheet has fromabout 1 to about 30 apertures per square cm, for example from about 4 toabout 15 apertures per square cm or from about 5 to about 10 aperturesper square cm. In certain embodiments the apertures are uniformlydiluted over the surface of the sheet, preferably in a regular pattern.The mean area of each aperture may for example be from about 0.01 toabout 10 mm², preferably from about 0.1 to about 4 mm², and morepreferably from about 1 mm² to about 2 mm². It will be appreciated thatthe sheet may include more than one size and shape of aperture in orderto provide apertures that open more or less quickly on exposure toinfected wound fluid. This enables still more control over the dynamicsof therapeutic agent delivery to the wound. Typically, substantially thewhole area of the apertures in the apertured sheet is blocked by thebarrier material before exposure to wound exudate

Preferably, the thickness of the barrier film or the apertured sheet (byASTM D374-79) is from about 0.2 to about 5 mm, more preferably fromabout 0.4 to about 3 mm.

For example, the barrier layer material may further comprise a polymerselected from the group consisting of water soluble macromolecularmaterials (hydrogels) such as sodium alginate, sodium hyaluronate,alginate derivatives such as the propylene glycol alginate described inEP-A-0613692, and soluble hydropolymers formed from vinyl alcohols,vinyl esters, vinyl ethers and carboxy vinyl monomers, meth(acrylic)acid, acrylamide. N-vinyl pyrrolidone, acylamidopropane sulphonic acid,PLURONIC (Registered Trade Mark) (block polyethylene glycol, blockpolypropylene glycol) polystyrene-, maleic acid, NN-dimethylacrylamidediacetone acrylamide, acryloyl morpholine, and mixtures thereof.Suitable hydrogels are also described in U.S. Pat. No. 5,352,508.

The barrier layer material may further comprise a polymer selected fromthe group consisting of bioerodible polymers such aspolylactide/polyglycolide, collagen, gelatin, polyacrylate gels such asthose described in EP-A-0676457, calcium alginate gels, crosslinkedhyaluronate gels, gels of alginate derivatives such as propylene glycolalginate, and gels wherein the hydropolymer is formed from vinylalcohols, vinyl esters, vinyl ethers and carboxy vinyl monomers,meth(acrylic) acid, acrylamide, N-vinyl pyrrolidone, acylamidopropanesulphonic acid, PLURONIC (Registered Trade Mark) (block polyethyleneglycol, block polypropylene glycol) polystyrene-, maleic acid,NN-dimethylacrylamide diacetone acrylamide, acryloyl morpholine, andmixtures thereof. Suitable hydrogels are also described in U.S. Pat. No.5,352,508.

The barrier layer material may further comprise from about 5 to about50% by weight, preferably from 16 to 40% by weight, on the same basis ofone or more humectants such as glycerol. The barrier layer material mayfurther contain up to about 30% w/w, more preferably up to about 15% w/won the same basis of water.

In certain embodiments wound dressings have a layered structure whereinpreferably a layer of the antimicrobial substance is provided behind thebarrier layer. That is to say, on the side of the barrier layer oppositeto the wound facing surface of the barrier layer in use. The layer ofantimicrobial substance may contact the barrier layer directly, or maybe separated therefrom for example by an absorbent layer.

Preferably, the barrier sheet according to these embodiments of theinvention forms part of a layered wound dressing having theantimicrobial material disposed on the side of the barrier sheetopposite to the wound facing side of the barrier sheet

Preferably, the layered wound dressing further comprises an absorbentlayer and/or a backing layer.

The area of the optional absorbent layer is typically in the range offrom 1 cm² to 200 cm², more preferably from 4 cm² to 100 cm².

The optional absorbent layer may be any of the layers conventionallyused for absorbing wound fluids, serum or blood in the wound healingart, including gauzes, nonwoven fabrics, superabsorbents, hydrogels andmixtures thereof. Preferably, the absorbent layer comprises a layer ofabsorbent foam, such as an open celled hydrophilic polyurethane foamprepared in accordance with EP-A-0541391. the entire content of which isexpressly incorporated herein by reference. In other embodiments, theabsorbent layer may be a nonwoven fibrous webs for example a carded webof viscose staple fibers. The basis weight of the absorbent layer may bein the range of 50-500 g/m², such as 100-400 g/m². The uncompressedthickness of the absorbent layer may be in the range a from 0.5 mm to 10mm, such as 1 mm to 4 mm. The free (uncompressed) liquid absorbencymeasured for physiological saline may be in the range of 5 to 30 g/g at25°. In certain embodiments the antimicrobial material may be dispersedin or on the absorbent layer.

Preferably the dressing further comprises a backing layer covering thebarrier sheet and the optional absorbent layer on the side opposite thewound-facing side of the dressing. The backing layer preferably providesa barrier to passage of microorganisms through the dressing and furtherpreferably blocks the escape of wound fluid from the dressing. Thebacking layer may extend beyond at least one edge of the barrier sheetand optional absorbent layer to provide an adhesive-coated marginadjacent to the said edge for adhering the dressing to a surface, suchas to the skin of a patient adjacent to the wound being treated. Anadhesive-coated margin may extend around all sides of the barrier sheetand optional absorbent layer, so that the dressing is a so-called islanddressing. However, it is not necessary for there to be anyadhesive-coated margin.

Preferably, the backing layer is substantially liquid-impermeable. Thebacking sheet is preferably semi-permeable. That is to say, be backingsheet is preferably permeable to water vapour, but not permeable toliquid water or wound exudate. Preferably, the backing sheet is alsomicroorganism-impermeable. Suitable continuous conformable backingsheets will preferably have a moisture vapor transmission rate (MVTR) ofthe backing sheet alone of 300 to 5000 g/m²/24 hrs, preferably 500 to2000 g/m²/24 hrs at 37.5 C at 100% to 10% relative humidity difference.The backing sheet thickness is preferably in the range of 10 to 1000micrometers, more preferably 100 to 500 micrometers.

Suitable polymers for forming the backing sheet include polyurethanesand poly alkoxyalkyl acrylates and methacrylates such as those disclosedin GB-A-1280631. Preferably, the backing sheet comprises a continuouslayer of a high density blocked polyurethane foam that is predominantlyclosed-cell. A suitable backing sheet material is the polyurethane filmavailable under the Registered Trade Mark ESTANE 5714F.

The adhesive layer (where present) should be moisture vapor transmittingand/or patterned to allow passage of water vapor therethrough. Theadhesive layer is preferably a continuous moisture vapor transmitting,pressure sensitive adhesive layer of the type conventionally used forisland-type wound dressings, for example, a pressure sensitive adhesivebased on acrylate ester copolymers, polyvinyl ethyl ether andpolyurethane as described for example in GB-A-1280631. The basis weightof the adhesive layer is preferably 20 to 250 g/m², and more preferably50 to 150 g/m². Polyurethane-based pressure sensitive adhesives arepreferred.

Preferably, the adhesive layer extends outwardly form the absorbentlayer and the envelope to form an adhesive-coated margin on the backingsheet around the absorbent layer as in a conventional island dressing.

Also within the scope of the present invention are embodiments in whichthe barrier layer substantially encapsulates the antimicrobialsubstance. For example, the dressing may comprise, or consistessentially of, particles such as microspheres of antimicrobial materialencapsulated in a layer comprising the substrate material. The particlesare preferably loaded with from 1 to 90 wt. %, more preferably from 3 to50 wt. % of the antimicrobial agents.

The particles may be made by any suitable technique, includingcomminution, coacervation, or two-phase systems for example as describedin U.S. Pat. No. 3,886,084. Techniques for the preparation of medicatedmicrospheres for drug delivery are reviewed, for example, in PolymericNanoparticles and Microspheres, Gulot and Couvreur eds., CRC Press(1986).

A preferred method for preparation of the microparticles iscoacervation, which is especially suited to the formation of particlesin the preferred size range of 100 to 500 micrometers having a highloading of therapeutic agents. Coacervation is the term applied to theability of a number of aqueous solutions of colloids, to separate intotwo liquid layers, one rich in colloid solute and the other poor incolloid solute. Factors which influence this liquid-liquid phaseseparation are: (a) the colloid concentration, (b) the solvent of thesystem, (c) the temperature, (d) the addition of anotherpolyelectrolyte, and (e) the addition of a simple electrolyte to thesolution. Coacervation can be of two general types. The first is called“simple” or “salt” coacervation where liquid phase separation occurs bythe addition of a simple electrolyte to a colloidal solution. The secondis termed “complex” coacervation where phase separation occurs by theaddition of a second colloidal species to a first colloidal solution,the particles of the two dispersed colloids being oppositely charged.Generally, materials capable of exhibiting an electric charge insolution (i.e. materials which possess an ionizable group) arecoacervable. Such materials include natural and synthetic macromolecularspecies such as gelatin, acacia, tragacanth, styrene-maleic anhydridecopolymers, methyl vinyl ether-maleic anhydride copolymers,polymethacrylic acid, and the like.

If, prior to the initiation of coacervation, a water-immisciblematerial, such as an oil, is dispersed as minute droplets in an aqueoussolution or sol or an encapsulating colloidal material, and then, asimple electrolyte, such as sodium sulfate, or another, oppositelycharged colloidal species is added to induce coacervation, theencapsulating colloidal material forms around each oil droplet, thusinvesting each of said droplets in a liquid coating of the coacervatedcolloid. The liquid coatings which surround the oil droplets musthereafter be hardened by cross-linking to produce solid-walledmicrocapsules

Preferably, the wound dressing according to any aspect of the presentinvention is sterile and packaged in a microrganism-impermeablecontainer.

An embodiment of the present invention will now be described further, byway of example, with reference to the accompanying drawings, in which:

FIG. 1 shows a perspective view of the lower (wound contacting) surfaceof a wound dressing according to the invention with the wound contactingsheet according to the invention partially cut away; and

FIG. 2 shows a plan view of a portion of the wound contacting sheetaccording to the invention from the dressing of FIG. 1.

Referring to FIG. 1, the wound dressing 1 is an island-typeself-adhesive wound dressing comprising a backing layer 2 of microporousliquid-impermeable polyurethane foam, such as ESTANE 5714F (RegisteredTrade Mark). The backing layer is permeable to water vapor, butimpermeable to wound exudate and microorganisms.

The backing layer 2 is coated with a substantially continuous layer 3 ofpressure sensitive polyurethane adhesive. An absorbent island 4continuing the antimicrobial is adhered to a central region of theadhesive-coated backing sheet 2.

The absorbent island 4 comprises an absorbent layer 5 of gauze having abasis weight of about 250 g/m² and impregnated with silver sulfadiazinein an amount of about 25 /m².

A wound contacting barrier sheet 6 extends over the absorbent layer 5and is wrapped around the absorbent layer 5, and adhered to the backinglayer 2 behind the absorbent layer 5 by the adhesive 3. The woundcontacting sheet 6 consists of a support layer 7 of a perforatedpolypropylene film with 12 perforations per cm² in which the apertures 8are occluded by a collagenase-degradable film composition prepared asfollows.

1 g of collagen fibers formed by freeze drying Type I collagen extractedfrom limed bovine hide were suspended in 100 ml of 0.05M acetic acid. 40ml of this suspension was poured into a 10 cm×10 cm square plastic dish.The dish was placed in a drying cabinet at room temperature until beweight of the container had reduced to 50% of the initial weight. Atthis stage the perforated polypropylene film with 12 perforations percm² was placed on the surface of the collagen suspension. The suspensionwas then fully dried and peeled from the square dish. The resultingmaterial had the apertures of the polypropylene film occluded by a thinfilm of Type I collagen.

The wound facing surface of the dressing shown in FIG. 1 is protected bytwo silicon-coated release papers 9,10. The dressing is packaged in amicroorganism-impermeable pouch (not shown), and sterilised using gammaradiation.

In use, the dressing 1 is removed from the package, the release papers9,10 are removed, and the dressing is adhered to the skin around thewound by the adhesive layer 3, with the wound contacting sheet incontact with the wound to provide a sterile and absorbent dressing. Thedissolution of the collagen in the presence of elevated levels ofcollagenase triggers the release of antimicrobial active agent from theabsorbent layer into the wound in response to increased collagenaseproduction by infected or chronic wounds. This has the further benefitof allowing excess exudate to escape through the perforated sheet 7 intothe absorbent layer 5.

The above embodiment has been described by way of example only. Manyother embodiments falling within the scope of the accompanying claimswill be apparent to the skilled reader.

1. A wound dressing comprising: a therapeutic agent selected from thegroup consisting of antimicrobial substances, pain relieving substances,protease inhibitors, and mixtures thereof; and a wound contactingbarrier layer for initially separating the therapeutic agent from awound fluid, said barrier layer comprising a substrate for an enzymefrom an infected or chronic wound selected from the group consisting ofproteases, kallikrein and tissue- plasminogen activator, wherein saidbarrier layer is substantially free of the therapeutic agent, issubstantially impervious to and insoluble in wound fluid free of saidenzyme and, in use, separates said therapeutic agent from said woundfluid until and unless said substrate is broken down by said enzyme froman infected or chronic wound.
 2. The wound dressing according to claim1, wherein the therapeutic substance comprises an antiseptic, anantibiotic, an analgesic, a local anaesthetic, a protease inhibitor, ormixtures thereof.
 3. The wound dressing according to claim 2, whereinthe therapeutic substance comprises an antiseptic selected from thegroup consisting of chlohexidine, silver sulfadiazine, povidone iodine,silver salts, triclosan, sucralfate, quaternary ammonium salts, andmixtures thereof.
 4. The wound dressing according to claim 2, whereinthe therapeutic substance comprises an antibiotic selected from thegroup consisting of tetracycline, penicillins, terramycins,erythromycin, bacitracin, neomycin, polymycin B, mupirocin, clindamycinand mixtures thereof.
 5. The wound dressing according to claim 1,further comprising a liquid-impermeable backing layer over thetherapeutic substance and the barrier layer.
 6. The wound dressingaccording to claim 5, wherein the backing layer is adhesive-coated andprovides an adhesive-coated margin around the therapeutic substance andthe barrier layer.
 7. The wound dressing according to claim 1, furthercomprising an absorbent layer.
 8. The wound dressing according to claim1, wherein the barrier layer comprises a substantially continuous filmcomprising the substrate material.
 9. The wound dressing according toclaim 1, wherein the barrier layer comprises an apertured sheet having acomposition comprising the substrate material applied thereto inocclusive fashion.
 10. The wound dressing according to claim 8 or 9,wherein a layer of the therapeutic substance is provided behind thebarrier layer.
 11. The wound dressing according to claim 10, wherein anabsorbent layer is provided behind the barrier layer and the therapeuticsubstance is dispersed in the absorbent layer.
 12. The wound dressingaccording to any one of claims 1 to 7, wherein the barrier layersubstantially encapsulates the therapeutic substance.
 13. The wounddressing according to any one of claims 1 to 9, wherein the substratematerial comprises a substance selected from the group consisting ofelastin, fibronectin, collagen, crossliniked gelatin, fibrinogen,casein, hyaluronic acid, plasminogen, fibrin, and mixtures thereof. 14.The wound dressing according to claim 10, wherein the substrate materialcomprises a substance selected from the group consisting of elastin,fibronectin, collagen, crossliniked gelatin, fibrinogen, casein,hyaluronic acid, plasminogen, fibrin, and mixtures thereof.
 15. Thewound dressing according to claim 11, wherein the substrate materialcomprises a substance selected from the group consisting of elastin,fibronectin, collagen, crossliniked gelatin, fibrinogen, casein,hyaluronic acid, plasminogen, fibrin, and mixtures thereof.
 16. Thewound dressing according to claim 12, wherein the substrate materialcomprises a substance selected from the group consisting of elastin,fibronectin, collagen, crossliniked gelatin, fibrinogen, casein,hyaluronic acid, plasminogen, fibrin, and mixtures thereof.
 17. A methodfor treating a wound, comprising providing a wound dressing according toclaim 1, and topically applying it to a wound.